This Program Grant consisting of four Projects, two scientific Cores and one Administrative Core is focused on testing the role of neutralizing antibodies and cellular immunity induced by infection or elicited by candidate vaccines comprising selected domains of the HIV and SIV envelopes for their ability to protect against virus challenge_. The challenge studies will be conducted In chimps and macaques housed in primate facilities at distant sites, while the virologic, immunologic and molecular studies will be done at Duke University. The major goal of these studies is to determine what role the principal neutralizing determinant (PND) of HIV which is situated within the V3 loop will play in protection against viral infection. Host responses to the PND Involving both the humoral and cellular arms will be determined and approaches to optimize these will be tested and refined. We also hope to uncover to what degree vaccine principles which are relevant to HIV-1 will apply to SIV and vice versa.